Botulinum toxin is a polypeptide product of the anaerobic bacterium Clostridium botulinum. The toxin causes muscle paralysis in mammals by blocking presynaptic release of the neurotransmitter acetylcholine at the neuromuscular junction. While the toxin has long been associated with fatal botulism, in recent years it has been used therapeutically to treat certain involuntary muscle movement disorders including focal dystonias (such as strabismus, essential blepharospasm and hemifacial spasm), as well as segmental dystonias (such as torticollis, oromandibular dystonia, and spasmodic dysphonia) and spasticity. The toxin has also found utility in various cosmetic indications, such as non-surgical reduction of “frown lines” on the face as well as in the treatment of hyperhydrosis (excessive perspiration).
Currently, there are two botulinum toxin (type A) preparations that are approved for therapeutic use in humans—“BOTOX®” (Oculinum®; Allergan Inc., Irvine, Calif.) and “DYSPORT®” (Spexwood Pharmaceuticals, Ltd.; U.K). Both these formulations are provided to clinicians in lyophilized (freeze-dried) form for reconstitution just prior to use.
Due to patient-to-patient variations in dosage requirements, the dosage needed for any individual patient may vary considerably. Moreover, for certain indications, the clinician must administer only a small fraction of the contents of a prepared vial over a protracted period of time, which may be several hours. Although one published study has indicated that liquid botulinum toxin formulations can be re-frozen and thawed with substantial retention of activity (Schantz and Kautter, 1978), more recent studies assessing the activity of the reconstituted toxin have demonstrated that “BOTOX®” loses at least 44% of its potency when it is reconstituted and stored under standard refrigerator (approximately 4° C.) for 12 hours. Moreover, when the reconstituted formulation was stored in a sub-zero freezer at −70° C., it lost about 70% of its potency after two weeks (Gartlan and Hoffman, 1993). For these reasons, it is recommended that such compositions not be used later than 4 hours after reconstitution. This can result in a significant waste of drug and cost to the patient.
There is therefore a need for a ready-to-use liquid formulation of botulinum toxin that can be conveniently shipped, stored and used as needed by the clinician. The present invention provides such a formulation.